High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in <i>Pex1</i>-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment
Genetic alterations in <i>PEX</i> genes lead to peroxisome biogenesis disorder. In humans, they are associated with Zellweger spectrum disorders (ZSD). No validated treatment has been shown to modify the dismal natural history of ZSD. Liver transplantation (LT) improved clinical and bioc...
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doaj-7e5ace1490694c9a82bf06b5a5c975d62020-12-31T00:00:56ZengMDPI AGCells2073-44092021-12-0110404010.3390/cells10010040High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in <i>Pex1</i>-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term EngraftmentTanguy Demaret0Jonathan Evraerts1Joachim Ravau2Martin Roumain3Giulio G. Muccioli4Mustapha Najimi5Etienne M. Sokal6Laboratoire d’Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, BelgiumLaboratoire d’Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, BelgiumLaboratoire d’Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, BelgiumBioanalysis and Pharmacology of Bioactive Lipids Research Group (BPBL), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), 1200 Brussels, BelgiumBioanalysis and Pharmacology of Bioactive Lipids Research Group (BPBL), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), 1200 Brussels, BelgiumLaboratoire d’Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, BelgiumLaboratoire d’Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, BelgiumGenetic alterations in <i>PEX</i> genes lead to peroxisome biogenesis disorder. In humans, they are associated with Zellweger spectrum disorders (ZSD). No validated treatment has been shown to modify the dismal natural history of ZSD. Liver transplantation (LT) improved clinical and biochemical outcomes in mild ZSD patients. Hepatocyte transplantation (HT), developed to overcome LT limitations, was performed in a mild ZSD 4-year-old child with encouraging short-term results. Here, we evaluated low dose (12.5 million hepatocytes/kg) and high dose (50 million hepatocytes/kg) syngeneic male HT via intrasplenic infusion in the <i>Pex1</i>-G844D NMRI mouse model which recapitulates a mild ZSD phenotype. HT was feasible and safe in growth retarded ZSD mice. Clinical (weight and food intake) and biochemical parameters (very long-chain fatty acids, abnormal bile acids, etc.) were in accordance with ZSD phenotype but they were not robustly modified by HT. As expected, one third of the infused cells were detected in the liver 24 h post-HT. No liver nor spleen microchimerism was detected after 7, 14 and 30 days. Future optimizations are required to improve hepatocyte engraftment in <i>Pex1</i>-G844D NMRI mouse liver. The mouse model exhibited the robustness required for ZSD liver-targeted therapies evaluation.https://www.mdpi.com/2073-4409/10/1/40peroxisome biogenesis disorderZellweger spectrum disorderoxysterolsmouse modelPEX1 p.Gly843AspPEX1 c.2528G> |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tanguy Demaret Jonathan Evraerts Joachim Ravau Martin Roumain Giulio G. Muccioli Mustapha Najimi Etienne M. Sokal |
spellingShingle |
Tanguy Demaret Jonathan Evraerts Joachim Ravau Martin Roumain Giulio G. Muccioli Mustapha Najimi Etienne M. Sokal High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in <i>Pex1</i>-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment Cells peroxisome biogenesis disorder Zellweger spectrum disorder oxysterols mouse model PEX1 p.Gly843Asp PEX1 c.2528G> |
author_facet |
Tanguy Demaret Jonathan Evraerts Joachim Ravau Martin Roumain Giulio G. Muccioli Mustapha Najimi Etienne M. Sokal |
author_sort |
Tanguy Demaret |
title |
High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in <i>Pex1</i>-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment |
title_short |
High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in <i>Pex1</i>-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment |
title_full |
High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in <i>Pex1</i>-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment |
title_fullStr |
High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in <i>Pex1</i>-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment |
title_full_unstemmed |
High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in <i>Pex1</i>-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment |
title_sort |
high dose versus low dose syngeneic hepatocyte transplantation in <i>pex1</i>-g844d nmri mouse model is safe but does not achieve long term engraftment |
publisher |
MDPI AG |
series |
Cells |
issn |
2073-4409 |
publishDate |
2021-12-01 |
description |
Genetic alterations in <i>PEX</i> genes lead to peroxisome biogenesis disorder. In humans, they are associated with Zellweger spectrum disorders (ZSD). No validated treatment has been shown to modify the dismal natural history of ZSD. Liver transplantation (LT) improved clinical and biochemical outcomes in mild ZSD patients. Hepatocyte transplantation (HT), developed to overcome LT limitations, was performed in a mild ZSD 4-year-old child with encouraging short-term results. Here, we evaluated low dose (12.5 million hepatocytes/kg) and high dose (50 million hepatocytes/kg) syngeneic male HT via intrasplenic infusion in the <i>Pex1</i>-G844D NMRI mouse model which recapitulates a mild ZSD phenotype. HT was feasible and safe in growth retarded ZSD mice. Clinical (weight and food intake) and biochemical parameters (very long-chain fatty acids, abnormal bile acids, etc.) were in accordance with ZSD phenotype but they were not robustly modified by HT. As expected, one third of the infused cells were detected in the liver 24 h post-HT. No liver nor spleen microchimerism was detected after 7, 14 and 30 days. Future optimizations are required to improve hepatocyte engraftment in <i>Pex1</i>-G844D NMRI mouse liver. The mouse model exhibited the robustness required for ZSD liver-targeted therapies evaluation. |
topic |
peroxisome biogenesis disorder Zellweger spectrum disorder oxysterols mouse model PEX1 p.Gly843Asp PEX1 c.2528G> |
url |
https://www.mdpi.com/2073-4409/10/1/40 |
work_keys_str_mv |
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